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Sunday, 13 March 2016

Apalutamide, ARN 509

Apalutamide.svg

Apalutamide,, ARN 509


 ARN-509;  cas 956104-40-8; ARN 509; UNII-4T36H88UA7;
ARN-509; JNJ-56021927; JNJ-927\
Phase III Prostate cancer
4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)PYRIDIN-3-YL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO[3.4]OCTAN-5-YL)-2-FLUORO-N-METHYLBENZAMIDE;
4-(7-(6-cyano-5-(trifluoroMethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspirooctan-5-yl)-2-fluoro-N-MethylbenzaMide;
4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
ARN-509 is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM, useful for prostate cancer treatment.
IC50 value: 16 nM
Target: androgen receptor
Molecular Formula:C21H15F4N5O2S
Molecular Weight:477.434713 g/mol
  • Originator University of California System
  • Developer Janssen Research & Development, Aragon Pharmaceuticals, Memorial Sloan Kettering Cancer Center
  • Class Antiandrogens; Antihormones; Antineoplastics; Aza compounds; Benzamides; Pyridines; Small molecules; Spiro compounds; Sulfhydryl compounds; Thiohydantoins
  • Mechanism of Action Androgen receptor antagonists; Hormone inhibitors
  • 03 Nov 2015 Janssen Research & Development plans a drug-interaction and pharmacokinetics phase I trial for Prostate cancer in Moldova (NCT02592317)
  • 01 Nov 2015 Phase-III clinical trials in Prostate cancer (Adjunctive treatment) in United Kingdom, Sweden, Poland, Hungary, Australia, Australia, Spain, Canada, Brazil, USA (PO) (NCT02489318; EudraCT2015-000735-32)
  • 15 Oct 2015 Aragon plans a phase I cardiac safety trial in patients with Prostate cancer in USA, Canada, the Netherlands and United Kingdom (NCT02578797)

Clinical Information of ARN-509

Product NameSponsor OnlyConditionStart DateEnd DatePhaseLast Change Date
ARN-509Aragon Pharmaceuticals IncHormone refractory prostate cancer31-JUL-1030-JUN-13Phase 217-SEP-13
Aragon Pharmaceuticals Inc31-MAR-1330-JUN-13Phase 117-SEP-13
Aragon Pharmaceuticals IncHormone refractory prostate cancer31-OCT-1331-DEC-16Phase 305-NOV-13
Aragon Pharmaceuticals Inc; Johnson & JohnsonHormone refractory prostate cancer28-FEB-1301-FEB-14Phase 107-OCT-13
Aragon Pharmaceuticals IncHormone dependent prostate cancer28-FEB-1328-FEB-18Phase 218-OCT-13

References on ARN-509

Apalutamide, also known as ARN-509 and JNJ-56021927 , is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
Apalutamide (INN) (developmental code name ARN-509, also JNJ-56021927) is a non-steroidal antiandrogen that is under development for the treatment of prostate cancer.[1] It is similar to enzalutamide both structurally and pharmacologically,[2] acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and reduced central nervous system permeation.[1][3][4] Apalutamide binds weakly to the GABAA receptor similarly to enzalutamide, but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[1][3][5] The drug has been found to be effective and well-tolerated in clinical trials thus far,[2][4] with the most common side effects reported including fatigue, nausea, abdominal pain, and diarrhea.[6][3][5] Apalutamide is currently in phase III clinical trials for castration-resistant prostate cancer.[7]
Recently, the acquired F876L mutation of the AR identified in advanced prostate cancer cells was found to confer resistance to both enzalutamide and apalutamide.[8][9] A newer antiandrogen, ODM-201, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.[10]
Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[2]
The chemical structure of ARN-509 is very similar structure to  that of Enzalutamide (MDV3100) with two minor modifications: (a) two methyl groups in the 5-member ring of MDV3100 is linked by a CH2 group in ARN-509; (b) the carbon atom in the benzene ring of MDV3100 is replaced by a nitrogen atom in ARN-509. ARN-509 is considered as a Me-Too drug of Enzalutamide (MDV3100). ARN-509 was claimed to be more active than Enzalutamide (MDV3100).
ARN-509 is a novel 2nd Generation anti-androgen that is targeted to treat castration resistant prostate cancers where 1st generation anti-androgens fail.  ARN-509 is unique in its action in that it inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA. Importantly, and in contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that over-express AR. ARN-509 is easily synthesized, and its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, its excellent preclinical safety profile makes it well suited as either a mono- or a combination therapy across the entire spectrum of prostate cancer disease states. (source: http://www.aragonpharm.com/programs/arn509.htm).
ARN-509 is  a competitive AR inhibitor, which is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509 , whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. (source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )
(source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )

 ARN-509.png

 

SYNTHESIS

str1

WO2007126765

WO 2008119015
WO2011103202
WO2014190895

PATENT

WO2011103202
http://www.google.com/patents/WO2011103202A2?cl=en

PATENT

WO2014190895


 

PATENT

US20100190991
Prostate cancer is one of the most common forms of cancer found in Western men and the second leading cause of cancer death in Western men. When prostate cancer is confined locally, the disease can usually be treated by surgery and/or radiation. Advanced disease is frequently treated with anti-androgen therapy, also known as androgen deprivation therapy. Administration of anti-androgens blocks androgen receptor (AR) function by competing for androgen binding; and therefore, anti-androgen therapy reduces AR activity. Frequently, such therapy fails after a time, and the cancer becomes hormone refractory, that is, the prostate cancer no longer responds to hormone therapy and the cancer does not require androgens to progress.
Overexpression of AR has been identified as a cause of hormone refractory prostate cancer (Nat. Med., 10:33-39, 2004; incorporated herein by reference). Overexpression of AR is sufficient to cause progression from hormone sensitive to hormone refractory prostate cancer, suggesting that better AR antagonists than the current drugs may be able to slow the progression of prostate cancer. It has been demonstrated that overexpression of AR converts anti-androgens from antagonists to agonists in hormone refractory prostate cancer. This work explains why anti-androgen therapy fails to prevent the progression of prostate cancer.
The identification of compounds that have a high potency to anatgonize AR activity would overcome the hormone refractory prostate cancer and slowdown the progression of hormone sensitive prostate cancer. Such compounds have been identified by Sayers et al. (WO 2007/126765, published Nov. 8, 2007; which is incorporated herein by reference). One compound is known as A52, a biarylthiohydantoin, and has the chemical structure
  • Figure US20100190991A1-20100729-C00001
    Another compound A51 has the chemical structure:
  • Both of these compounds share the same western and central portions. Given the need for larger quantities of pure A51 and A52 for pre-clinical and clinical studies, there remains a need for a more efficient synthesis of the compound from commercially available starting materials.

Convergent Coupling to Yield A52

The final coupling step between intermediates A and B is achieved by microwave irradiation and cyclization to the biarylthiohydantoin A52 (Scheme 6). Although 3 equivalents of A are required for the highest yields in this transformation, the un-reacted amine A can be recovered.

Experimental Section 2-cyano-5-nitro-3-trifluoromethylpyridine

  • Figure US20100190991A1-20100729-C00125
    Zinc cyanide (25 mg, 0.216 mmol, 1.2 eq) is added to the chloride (43 mg, 0.180 mmol) solubilized in DMF (1 ml). The solution is degassed for 10 minutes. Then the ligand dppf (20 mg, 0.036 mmol, 0.2 eq) is added. The solution is degassed again for 5 min. The catalyst Pd2(dba)3 (25 mg, 0.027 mmol, 0.15 eq) is added, the solution is degassed for 5 more minutes. The reaction mixture is then heated at 130° C. for 20 min in a microwave. After filtration, the solvent is evaporated and the crude residue is purified by flash chromatography on silica gel (hexane/EtOAc) to afford 16 mg (40%) of the desired product
  • 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.5, 1H); 9.08 (d, J=2.5, 1H),

5-amino-2-cyano-3-trifluoromethylpyridine

  • 2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in 1:1 EtOAc/AcOH (1 mL) and heated to 65° C. Iron powder (9 mg, 0.161 μmol, 5 eq, 325 mesh) is added and the mixture stirred for 2 hours. The mixture is filtered through celite, and the filtrate is concentrated under vacuo. The crude residue is purified by flash chromatography on silica gel (hexane/EtOAc) to afford 4 mg (67%) of the desired product
  • 1H NMR (400 MHz CDCl3) δ 7.20 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H).

5-iodo-3-trifluoromethyl-2-pyridinol

  • 3-trifluoromethyl-2-pyridinol (25 g, 153.3 mmol) is dissolved in anhydrous CH3CN (150 mL) and DMF (150 mL). N-iodosuccinimide (34.5 g, 153 mmol) is then added. The reaction mixture is stirred at 80° C. for 2 hours and cooled to room temperature. Aqueous 1 M NaHCO3 (150 mL) is then added to the cooled mixture. After stirring for 5 min, the solvents are evaporated to dryness. Water is added and the aqueous phase is extracted (×2) with dichloromethane. The organic phase is then evaporated and the desired product is recrystallized in water to afford 36.2 g (81%) of a white powder.
  • 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=2.3, 1H); 7.98 (d, J=2.3, 1H), 13.41 (br s, 1H); 13C NMR (250 MHz CDCl3) δ 63.0, 121.4 (q, JC-F=272.3 Hz), 122.2 (q, JC-F=31.6 Hz), 144.4, 148.1 q, (JC-F=5.0 Hz), 160.1.

2-chloro-5-iodo-3-trifluoromethylpyridine

  • To an ice-cold mixture of POCl3 (1.60 mL) and DMF (1 mL) in a microwave vial, 5-iodo-3-trifluoromethyl-2-pyridinol (1 g, 3.47 mmol) is added. The vial is sealed and heated 20 min at 110° C. The reaction mixture cooled at room temperature is poured into ice cold water. The product precipitates. The precipitate is filtered, washed with cold water and dried to afford 661 mg (62%) of a light brown powder.
  • 1H NMR (500 MHz CDCl3) δ 8.32 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H). 13C NMR (250 MHz CDCl3) δ 89.4, 121.2 (q, JC-F=273.3 Hz), 126.8 (q, JC-F=33.6 Hz), 144.34, 148.5, 158.7.

2-choro-3-trifluoromethyl-N-paramethoxybenzylpyridin-5-amine

  • 2-choro-5-iodo-3-trifluoromethylpyridine is dried under vacuum. To a slurry of chloroiodpyridine (10 g, 32.6 mmol) in toluene (anhydrous) (98 mL) is added sequentially. Pd(OAc)2 (220 mg, 0.98 mmol, 0.03 eq), rac-BINAP (609 mg, 0.98 mmol, 0.03 eq) solid Cs2CO3 (53 g, 163 mmol, 5 eq), paramethoxybenzylamine (4.05 mL, 30.9 mmol, 0.95 eq) and triethylamine (0.41 mL, 2.93 mmol, 0.09 eq). The resulting slurry is degassed (×2) by vacuum/Argon backfills. The mixture is heated to reflux overnight. The mixture is then cooled to room temperature and H2O is added. The layers are separated and the toluene layer is concentrated under vacuo. The residue is purified by flash chromatography on silica gel (Hexane/EtOac; 95:5 to 30/70) to afford 4 g of white solid desired compound (40%).
  • 1H NMR (500 MHz CDCl3) δ 3.81 (s, 3H), 4.29 (d, J=5.1 Hz, 2H), 4.32 (br s, 1H), 6.90 (d, J=8.1 Hz, 2H), 7.19 (d, J=2.9 Hz, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.92 (d, J=2.9 Hz, 1H). 13C NMR (250 MHz CDCl3) δ 47.3, 55.4, 114.3, 119.3 (q, JC-F=5.1 Hz), 122.3 (q, JC-F=272.9 Hz), 124.80 (q, JC-F=32.7 Hz), 128.8, 129.1, 135.1, 136.6, 142.9, 159.3.

Alternative Synthesis of Intermediate K:

  • A suspension of vacuum dried 2-choro-5-iodo-3-trifluoromethylpyridine (50 g, 163 mmol) in anhydrous toluene (1,500 mL) was treated sequentially with Pd2(dba)3 (2.98 g, 3.25 mmol, 0.02 eq), Xantphos (5.65 g, 9.76 mmol, 0.06 eq), solid t-BuONa (23.4 g, 243 mmol, 1.5 eq), and paramethoxybenzylamine (23.2 mL, 179 mmol, 1.1 eq). The resulting slurry is degassed by vacuum/argon backfills for 10 min. The mixture is then quickly brought to reflux by a pre-heated oil bath. After 1.5 hours at this temperature, the mixture was cooled to the ambiant, and the solids were removed by filtration over a packed bed of celite and washed with toluene. The filtrate was then diluted with EtOAc (200 mL), then washed with H2O. The organic layer was concentrated under reduced pressure gave an oily solid. Crystallization from DCM/Hexane gave (36.6 g, 71%) of B as a light yellow solid.
  • Alternatively, smaller scales (5 to 10 gr of A) were purified by column silica gel chromatography using the gradient system Hexane-EtOAc 19-1 to 3-7 (v-v). This gave yields in excess of 85% of B as a white solid.

2-cyano-3-trifluoromethyl-N-paramethoxybenzylpyridin-5-amine

  • Zinc cyanide (0.45 g, 3.80 mmol, 1.2 eq) is added to the chloride (1 g, 3.16 mmol) solubilized in DMF (20 ml). The solution is degassed for 10 minutes. Then the ligand dppf (0.35 g, 0.63 mmol, 0.2 eq) is added. The solution is degassed again for 5 min. The catalyst Pd2(dba)3 (0.29 g, 0.32 mmol, 0.1 eq) is added, the solution is degassed for 5 more minutes. The reaction mixture is then heated at 150° C. for 10 min. After filtration, the solvent is evaporated and the crude residue is purified by flash chromatography on silica gel (hexane/EtOAc) to afford 900 mg (93%) of a dark yellow oil.
  • 1H NMR (500 MHz CDCl3) δ 3.82 (s, 3H), 4.37 (d, J=5.3 Hz, 2H), 4.93 (br s, 1H), 6.92 (d, J=9.5, 2H), 7.08 (d, J=2.7 Hz, 1H), 7.25 (d, J=9.5, 2H), 8.17 (d, J=2.7 Hz, 1H). 13C NMR (250 MHz CDCl3) δ 46.7, 55.4, 113.9, 114.5, 115.9, 116.1, 122.0 (q, JC-F=274.5 Hz), 128.0, 128.9, 131.4 (q, JC-F=33.1 Hz), 138.68, 145.9, 159.5.

5-amino-2-cyano-3-trifluoromethylpyridine H

  • TFA (1 mL) is added dropwise to a solution of pyridine L (83 mg, 0.27 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively.
  • 1H NMR (500 MHz CDCl3) δ 7.20 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H).

Scale Up and Purification of H

  • For the larger scales, an improved process calls for dissolving pyridine L (53 g, 0.172 mol) in TFA/DCM (170 mL, 4:1) at room temperature. Upon reaction completion (approximately 2 hours at room temperature), the volatiles were removed under reduced pressure. The residue is then diluted with EtOAc (800 mL), and washed with saturated aqueous NaHCO3. Vacuum concentration and precipitation from DCM-Hexane (1-2, v-v) gave a relatively clean product. Further washing with DCM gave pure intermediate H as a white solid (27.43 g, 85%).

Methyl 2,4-difluorobenzylamide

  • Methylamine 2M in THF (12.4 mL, 1.1 eq) is added to neat 2,4-difluorobenzoyl chloride (4 g, 22.6 mmol). The reaction mixture is stirred overnight at room temperature. The solvent is evaporated, ethyl acetate is added to solubilize the residue. The organic is washed with aqueous NaHCO3, dried with Na2SO4, filtered and evaporated to afford the quantitatively the desired compound as a white powder.
  • 1H NMR (500 MHz CDCl3) δ 3.00 (d, J=4.8 Hz, 3H), 6.84 (m, J=2.3; 10.3 Hz, 1H), 6.97 (m, J=2.3; 8.2 Hz, 1H), 8.08 (td, J=6.8; 8.9 Hz, 1H)
  • 13C NMR (100 MHz CDCl3) δ 27.0, 104.3 (d, J=26.0 Hz), 104.6 (d, J=25.9 Hz), 112.4 (dd, J=21.2; 3.1 Hz), 118.1 (dd, J=12.4; 3.8 Hz), 133.7 (dd, J=10.1; 3.9 Hz), 162.9 (dd, J=381.1; 12.3 Hz), 163.5.

Methyl 2-fluoro-4-paramethoxybenzylamine-benzylamide

  • Paramethoxybenzylamine (0.069 mL, 0.548 mmol, 2 eq) is added to methyl 2,4-difluorobenzylamide (47 mg, 0.274 mmol) dissolved in dimethylsulfoxide (0.5 mL). The reaction mixture is heated at 190° C. for 20 min in a microwave. After completion the solvent is evaporated and the residue is purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 18 mg (20%) of the desired product.
  • 1H NMR (500 MHz CDCl3) δ 2.98 (d, J=4.5 Hz, 3H), 3.81 (s, 3H), 4.26 (d, J=5.3 Hz, 2H), 4.47 (br s, 1H), 6.23 (dd, J=2.2; 15.1 Hz, 1H), 6.45 (dd, J=2.2; 8.7 Hz, 1H), 6.58 (br s, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.91 (t, J=9.0 Hz, 1H). 13C NMR (500 MHz CDCl3) δ 26.6, 47.3, 55.3, 98.2 (d, J=29.7 Hz), 109.25, 114.4, 128.6, 129.9, 133.1 (d, J=4.5 Hz), 152.3 (d, J=12.5 Hz), 159.1, 161.5, 163.9 (d, J=244 Hz), 164.5.

Methyl 4-amino-2-fluoro-benzylamide

  • TFA (1 mL) is added dropwise to a solution of methylamide (60 mg, 0.21 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively.
  • 1H NMR (500 MHz CDCl3) δ 2.98 (d, J=4.8 Hz, 3H), 4.15 (br s, 2H), 6.32 (d, J=14.3 Hz, 1H), 6.48 (d, J=8.2 Hz, 1H), 6.61 (br s, 1H), 7.90 (dd, J=8.6 Hz, 1H), 13C NMR (500 MHz CDCl3) δ 26.63, 100.8 (d, J=28.8 Hz), 110.3 (d, J=244.6 Hz), 110.9, 133.3 (d, J=4.3 Hz), 151.4 (d, J=12.5 Hz), 162.2 (d, J=244.6 Hz), 164.3 (d, J=3.5 Hz).

Synthesis of N-methyl-4-[7-(6-cyano-5-trifluoromethylpyridin-2-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluorobenzamide (A52) One Pot Small Scale (2.8 gr) Thiohydantoin Formation in DMF

  • Thiophosgene (1.2 mL, 1.16 eq, 15.6 mmol) is added dropwise to a solution of 5-amino-2-cyano-3-trifluoromethylpyridine (2.8 g, 1.1 eq, 15.0 mmol) and N-methyl-4-(1-cyanocyclobutylamino)-2-fluorobenzamide (3.35 g, 13.5 mmol) in dry DMF (25 mL) under Argon. The solution is stirred overnight at 60° C. To this mixture were added MeOH (60 mL) and aq. 2M HCl (30 mL), then the mixture was reflux for 2 h. After cooling to rt, the mixture was poured into ice water (100 mL) and extracted with EtOAc (3×60 mL). The organic layer was dried over Mg2SO4, concentrated and chromatographed on silica gel using 5% acetone in DCM to yield the desired product (2.65 g, 41%).

Alternative Synthesis of A52

  • Figure US20100190991A1-20100729-C00136
    Thiophosgene (1.23 mL, 16.0 mmol) is added dropwise to a solution of 5-amino-2-cyano-3-trifluoromethylpyridine (3.0 g, 16.0 mmol) and N-methyl-4-(1-cyanocyclobutylamino)-2-fluorobenzamide (3.96 g, 16.0 mmol) in dry DMA (35 mL) under Argon. The solution is stirred overnight at 60° C. To this mixture were added MeOH (60 mL) and aq. 2M HCl (30 mL), then it was brought to reflux temperature for 2 h. After cooling down to the ambiant, the mixture was poured into ice water (100 mL) and extracted with EtOAc (3×60 mL). The organic layer was dried over Mg2SO4, filtered over celite, and concentrated under reduced pressure. Silica gel chromatography using DCM/-acetone 19-1 (v-v) yielded the desired product (5.78 g, 76%).

Scale Up

  • Thiophosgene (5.48 mL, 1.05 eq, 70.9 mmol) is added dropwise to a solution of 5-amino-2-cyano-3-trifluoromethylpyridine (13.27 g, 1.05 eq, 70.9 mmol) and N-methyl-4-(1-cyanocyclobutylamino)-2-fluorobenzamide (16.7 g, 67.5 mmol) in dry DMA (110 mL) under Argon at 0° C. After 10 min, the solution was heated up to 60° C. and allowed to stir at that temperature for an overnight period. This was then diluted with MeOH (200 mL) and treated with aq. 2M HCl (140 mL), then the mixture was refluxed for 2 h. After cooling down to RT, the mixture was poured into ice water (500 mL), and filtered over buchner. The solid was recrystallized from DCM/EtOH to get desired product (20.6 g, 64%).

References


Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep 5: 12007. doi:10.1038/srep12007. PMC 4490394. PMID 26137992
11Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher  HI, Smith-Jones PM, Klang M, Smith ND, de Stanchina E, Wu N, Ouerfelli O, Rix P, Heyman R, Jung ME, Sawyers CL, Hager JH. ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-1503. Epub 2012 Jan 20.PubMed  PMID: 22266222.

12]. Clegg NJ, Wongvipat J, Joseph JD et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-503.
[13]. Courtney KD, Taplin ME. The evolving paradigm of second-line hormonal therapy options for castration-resistant prostate cancer. Curr Opin Oncol. 2012 May;24(3):272-7.
[14]. Schweizer MT, Antonarakis ES. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. Ther Adv Urol. 2012 Aug;4(4):167-78.
[15]. Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 in Castration-Resistant Prostate Cancer (CRPC)
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Apalutamide
Apalutamide.svg
Systematic (IUPAC) name
4-[7-[6-Cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
Clinical data
Pregnancy
category
  • X (Contraindicated)
Routes of
administration		Oral
Identifiers
CAS Number956104-40-8
ATC codeNone
PubChemCID 24872560
ChemSpider28424131
Chemical data
FormulaC21H15F4N5O2S
Molar mass477.434713 g/mol
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CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
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Liarozole

File:Liarozole.svg
Liarozole
CAS Registry Number: 115575-11-6
CAS Name: 5-[(3-Chlorophenyl)-1H-imidazol-1-ylmethyl]-1H-benzimidazole
Additional Names: (±)-5-(m-chloro-a-imidazol-1-ylbenzyl)benzimidazole
Molecular Formula: C17H13ClN4
Molecular Weight: 308.76
Percent Composition: C 66.13%, H 4.24%, Cl 11.48%, N 18.15%
Melting point: mp 108.2°
 
Derivative Type: Fumarate
CAS Registry Number: 145858-52-2
Manufacturers' Codes: R-85246
Trademarks: Liazal (Janssen)
Molecular Formula: 2C17H13ClN4.3C4H4O4
Molecular Weight: 965.75
Percent Composition: C 57.21%, H 3.97%, Cl 7.34%, N 11.60%, O 19.88%
 
Derivative Type: Hydrochloride
CAS Registry Number: 145858-50-0
Manufacturers' Codes: R-75251
Molecular Formula: C17H13ClN4.HCl
Molecular Weight: 345.23
Percent Composition: C 59.14%, H 4.09%, Cl 20.54%, N 16.23%
Therap-Cat: Antineoplastic.

 
Liarozole synthesis from Lednicer book 6 (Drugs of the Future citation).

Liarozole fumarate is prepared as shown in Scheme 20970301a. Anisol is reacted with 3-chlorobenzoyl chloride (I) under Friedel-Craft conditions to give (3-chlorophenyl)(4-methoxyphenyl)methanone (II). Nitration of (II) is carried out in dichloromethane at 10 C to yield (III). The methoxy group in (III) is replaced by the amino group by means of NH3 in 2-propanol at 100 C under pressure, giving (IV). By reduction of the keto function of (IV) with sodium borohydride in 2-propanol, the corresponding alcohol (V) is obtained, which upon treatment with 1,1'-carbonyldiimidazole in refluxing dichloromethane yields the imidazolyl compound (VI). Hydrogenation of the nitro group in (VI), followed by cyclization of (VII) in a refluxing mixture of formic acid and 4N hydrochloric acid, gives the benzimidazole derivative (VIII). Finally, the treatment of (VIII) with fumaric acid in ethanol yields liarozole fumarate (IX).

http://www.google.com/patents/WO1995022540A1?cl=en
Liarozole is a racemic mixture, i.e. a mixture of its optical isomers, and is specifically mentioned as compound 28 in EP-0,371,559. Said patent application mentions the use of compounds like liarozole in the treatment of epithelial disorders. EP-0,260,744 describes the use of compounds like liarozole for inhibiting or lowering androgen formation. Whereas EP-0,371,559 and EP-0,260,744 recognize that compounds like liarozole have stereochemically isomeric forms, no example of an enantiomerically pure form is given of liarozole.
Chemically liarozole is (±)-5-[3-chlorophenyl]-lH-imidazol-l-ylmethyl]-lH-benz- imidazole, and is represented by formula (I). As can be seen from the chemical structure, liarozole has one stereogenic center (indicated with an asterisk in formula (I)).
Figure imgf000003_0001
The subject of this invention is the enantiomerically pure dextrorotatory isomer or (+)-isomer of liarozole. Said isomer will hereinafter be referred to as (+)-liarozole. Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is iaevorotatory and with (+) or d meaning that the compound is dextrorotatory. For a given chemical structure the optically active isomers having an opposite sign of optical rotation are called enantiomers. Said enantiomers are identical except that they are mirror images of one another. A 1: 1 -mixture of such enantiomers is called a racemic mixture.
General preparation of structures including liarozole have been extensively described in EP-0,371,559 and EP-0,260,744.
Enantiomerically pure (+)-liarozole may be prepared by reacting an enantiomerically pure intermediate diamine of formula (B)-(II) with formic acid or a functional derivative thereof.
Figure imgf000005_0001
Said functional derivative of formic acid is meant to comprise the halide, anhydride, amide and ester, including the ortho and imino ester form thereof. Also methanimidamide or an acid addition salt thereof can be used as cyclizing agent.
The general reaction conditions, work-up procedures and conventional isolation techniques for carrying out the above and following reactions are described in the prior art. When more specific conditions are required they are mentioned hereinunder. The enantiomerically pure intermediate diamine of formula (B)-(II) may be prepared by reducing an intermediate of formula (B)-(iπ) by a standard nitro-to-amine reduction reaction.
Figure imgf000006_0001
The desired enantiomer of the intermediate of formula (B)-(]H) can be prepared by fractional crystallization of a racemic mixture of the intermediate of formula (HI) with an enantiomerically pure chiral acid. Preferred chiral acid for the above fractional crystallization is 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid (i.e. 10-camphorsulfonic acid).
Appropriate solvents for carrying out said fractional crystallization are water, ketones, e.g. 2-propane, 2-butanone; alcohols, e.g. methanol, ethanol, 2-propanol. Mixtures of ketones and water are very suitable for the above fractional crystallization. Preferably a mixture of 2-propanone and water is used.
The ratio of water/2-propanone by volume may vary from 1/10 to 1/2. Preferred range of said ratio is 1/5 to 1/3.
The fractional crystallizations are suitably carried out below room temperature, preferably below 5°C.
It was also found that the subsequent reaction step can be carried out without any appreciable racemization.
Alternatively the (+)-isomer of the compound of formula (I) may be prepared by cyclizing an intermediate of formula (B)-(IV) following procedures as described above for the cyclization of intermediates of formula (B)-(II) and desulfurating the thus obtained intermediate of formula (B)-(V). In formulas (B)-(TV) and (B)-(V) R represents Ci^alkyl, wherein Ci-^alkyl means a straight or branch chained saturated hydrocarbon radicals having 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl. Preferably R is methyl.
Figure imgf000007_0001
The intermediates of formula (B)-(IV) may be prepared by reacting an intermediate of formula (B)-(VI) with a reagent of formula (VII), alkylating the thus formed thiourea derivative of formula (B)-(VIII) subsequently cyclizing the intermediate of formula
(B)-(D ), and reducing the nitro group of the intermediate (B)-(X). In the formulas
(Vπ), (B)-(Vm), (B)-(IX) and (B)-(X) R represents Ci^alkyl as defined hereinabove.
S OR
Figure imgf000007_0002
(B)-(IV)
Experimental part
A. Preparation of the intermediates
Example 1 a) A heterogeneous mixture of (±)-4-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-2- nitrobenzenamine (the preparation of which is described in EP-371,559) (500 g) in
2-propanone (2000 ml) and water (100 ml) was stirred at 22°C. (-)-(lR)-7,7-dimethyl- 2-oxo-bicyclo[2.2.1]heptane-l-methanesulfonic acid (353.2 g) was added and the mixture became homogeneous after 10 minutes. The mixture was first stirred for 18 hours at 20°C and then for 3 hours at 0-5°C. The precipitate was filtered off, washed with 2-propanone/water 95/5 (150 ml) and dried, yielding 308.9 g (36.2%) of product A sample (306.7 g) was partitioned between dichloromethane (500 ml) and water (750 ml). Ammonium hydroxide (100 ml) was added. This mixture was stirred for 15 minutes. The aqueous layer was separated and extracted twice with dichloromethane (250 ml each time). The separated organic layer was washed with water (250 ml), dried, filtered and the solvent was evaporated, yielding 179.7 g of (-)-(B)-4-[(3-chlorophenyl)-
20 lH-imidazol-l-ylmethyl]-2-nitrobenzenamine; mp. 89.8°C; [α]D = -19.80° (c = 0.5% in methanol) (interm. 1). b) A mixture of intermediate (1)(179.7 g) in methanol (656 ml) and a solution of ammonia in methanol (32.7 ml) was hydrogenated at 20-25 °C with platinum on activated carbon (13.1 g) as a catalyst in the presence of thiophene (0.27 g). After uptake of hydrogen (3 eq.) the catalyst was filtered off and washed with 2-propanol (30 ml). A solution of hydrochloric acid in 2-propanol (522 ml) was added to the filtrate at <30°C. The mixture was stirred for 3 hours at 20 °C, then for 3 hours at 0-5 °C. The resulting precipitate was slowly filtered off, washed with methanol (100 ml) and dried
(50 °C), yielding 185.60 g (83.2%) (+)-(B)-4-[(3-chlorophenyl)-lH-imidazol-l-yl-
20 methyl]- 1,2-benzenediamine trihydrochloride; mp. 172.5°C; [α^ = +23.73° (c = 1% in methanol) (interm. 2).
Example 2 a) A mixture of (4-amino-3-nitrophenyl) (3-chlorophenyl)methanone (50 g), formamide (375 ml) and formic acid (63 ml) was stiιτed and refluxed for 17 hours. After cooling, the mixture was poured on ice. The precipitate was filtered off and dried, yielding 55 g (99.4%) of (±)-N-[(4-amino-3-nitrophenyl) (3-chlorophenyl)methyl]formamide (interm. 3). b) A mixture of intermediate (3) (50.7 g), hydrochloric acid 6N (350 ml) and 2-propanol (70 ml) was stirred and refluxed for 17 hours. The yellow precipitate was filtered off and dried in vacuo, yielding 51 g (97.8%) of (±)-4-amino-α-(3-chloro- phenyl)-3-nitrobenzenemethanamine monohydrochloride; mp. 263°C (interm.4). c) To a solution of intermediate (4) (43 g) in tetrahydrofuran (400 ml) at room temperature was added succesively N,N-diethylethanamine (13.8 g) and (R)-(-)-α- hydroxybenzeneacetic acid (20.8 g). Then a solution of 1-hydroxybenzotriazole monohydrate (22.2 g) in tetrahydrofuran (200 ml) was added. After complete addition a solution of N,N'-dicyclohexylcarbodiimide (33.9 g) in dichloromethane (300 ml) was introduced to the mixture. After stirring for 2 hours at room temperature N,N'- dicyclohexylurea was filtered off. The filtrate was washed with a solution of potassium carbonate (10%) and the organic layer was dried to give a mixture of diastereomers (60g) (fraction 1). The same experiment with intermediate (4) (16 g) as starting material resulted in a yield of 26 g of a mixture of diastereomers (fraction 2). Fraction 1 and 2 were combined and purified by HPLC (eluent : CH2θ2/ethyl acetate 90:10), yielding 30g (32.3%) of (±)-(R,B)-N-[(4-amino-3-nitrophenyl)(3-chlorophenyl)methyl]-α- hydroxybenzeneacetamide (interm.5). d) A mixture of intermediate (5) (30 g), hydrochloric acid 12N (300 ml) and 1-propanol (100 ml) was stirred and refluxed for 17 hours and poured on ice. The mixture was extracted with ethyl acetate. The aqueous phase was basified with ammonium hydroxide and extracted with dichloromethane. The dichloromethane extracts were dried, filtered and evaporated, yielding 7.3 g (36.0%) of (+)-(B)-4-amino-α-(3-chlorophenyl)-3- nitrobenzenemethanamine (interm. 6). e) A mixture of intermediate (6) (7.3 g), 2-isothiocyanato-l,l-dimethoxyethane (4.8 g) and methanol (75 ml) was stirred and refluxed for 2 hours. The mixture was evaporated to an oily residue, yielding 11 g (100%) of (+)-(B)-N-[(4-amino-3-nitrophenyl)(3- chlorophenyl)methyl]-N'-(2,2-dimethoxyethyl)thiourea (interm.7). f) A mixture of intermediate (7) (11 g), iodomethane (2 ml) and potassium carbonate (4.97 g) was stirred at room temperature for 48 hours. The solvent was evaporated and the residue was taken off with dichloromethane and washed with water. The organic layer was dried, filtered and evaporated, yielding 11.4 g of (+)-(S)-methyl (B)-N- [(4-amino-3-nitrophenyl)(3-chlorophenyl)methyl]-N'-(2,2-dimethoxyethyl)carbam- imidothioate as an oily residue (interm. 8). g) To intermediate (8) (11.4 g) at 0°C was added sulfuric acid (100ml) (precooled to 5°C). The mixture was stirred at 5°C until complete dissolution and then was warmed to room temperature. After stirring for 2 hours, the solution was poured on ice and basified with ammonium hydroxide. The aqueous solution was extracted with ethyl acetate. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (eluent : CH2CI2/CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 3.7 g (38.0%) of (+)-(B)-4-[(3-chlorophenyl)[2-(methylthio)-lH- imidazol-l-yl]methyl]-2-nitrobenzenamine (interm.9). h) A mixture of intermediate (9) (6.2 g), Raney nickel (6 g) and methanol (100 ml) was hydrogenated for 2 hours at 2 bar and at room temperature. After the calculated amount of hydrogen was taken up, the catalyst was filtered off. The filtrate, (+)-(B)-4-[(3- chlorophenyl)[2-(methylthio)-lH-imidazol-l-yl]methyl]-l,2-benzenediamine (interm. 10), was used for the next step. i) A mixture of intermediate (10) (5.7 g), methanimidamide monoacetate (5.2 g) and methanol (100 ml) was stirred and refluxed for 3 hours. The reaction mixture was evaporated and the residue was taken off in dichloromethane and washed with sodium hydrogen carbonate (10%). The organic layer was dried, filtered and evaporated. The oily residue was purified by column chromatography (eluent : CH2CI2/CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 4.9 g (83.7%) of (+)-(B)-5-[(3-cWorophenyl)[2-(methylthio)-lH-imidazol-l-yl]methyl]-lH-benzimidazole (interm. 11).
B. Preparation of the final compounds Example 3
A mixture of intermediate (2) (185 g) in water (512 ml) was stirred at 20 °C. Hydrochloric acid (289 ml) was added. Formic acid (85%) (61.17 ml) was added and this mixture was heated to 55°C. The reaction mixture was stirred for 3 hours at 55 °C and then cooled to 20°C. Dichloromethane (1223 ml) was added. Ammonium hydroxide (730 ml) was added dropwise at < 25°C. The separated organic layer was washed with water (500 ml), dried, filtered and the solvent was evaporated, yielding 152.88 g (108.5%) of product. A sample was dried (18 hours at 55 °C), yielding 3.18 g of (+)-(B)-5-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-lH-benzimidazole; mp.
20 113.7°C; [αjj = +43.46° (c = 1% in methanol) (comp. 1).
Example 4
A mixture of intermediate (11) (4.9 g), Raney nickel (2 g) and ethanol (100ml) was stirred and refluxed for 5 days, while every day an additional amount of Raney nickel (2 g) was added. The catalyst was filtered off and rinsed with dichloromethane. The filtrate was evaporated and the residue was purified twice by column chromatography (silica gel; CH2CI2/CH3OH 95:5 ; CH2CI2/CH3OH NH4OH 80:20:3). The eluent of the desired fraction was evaporated and the residue was converted into the hydrochloride salt in 2-propanol and ethanol. The salt was recrystallized from 2-butanone, yielding 1.8 g (37.2%) of (+)-(B)-5-[(3-chlorophenyl)(lH-imidazol-l-yl)methyl]-lH-benzimidazole
20 monohydrochloride; mp. 212.1°C; [α]D = +42.43° (c = 1% in ethanol) (comp. 2)
Example 5
Compound (1) (149.7 g) was dissolved in 2-butanone (2424 ml). A mixture of hydrochloric acid in 2-propanol (82.6 ml) in 2-butanone (727 ml) was added over a 2 hour period at 20 °C. The reaction mixture was stirred for 16 hours at 20 °C. The precipitate was filtered off, washed with 2-butanone (242 ml) and dried (vacuum; 80°C); yielding 147.5 g (99.3%) of (+)-(B)-5-[(3-chlorophenyl)-lH-imidazol-l-ylmethyl]-lH-
20 benzimidazole monohydrochloride; mp. 214.5°C; [α] j = +36.20° (c = 1% in methanol) (comp. 2). Example 6
A mixture of compound (1) (0.72 g) in ethanol (5.1 ml; denaturated) was stirred at 20 °C until it became homogeneous. (E)-2-butenedioic acid (0.54 g) was added The mixture was stirred for 18 hours at 20 °C and then cooled 0-5 °C and precipitation resulted. More denaturated ethanol (2 ml) was added and the mixture was stirred for 2 hours at 20 °C. The precipitate was filtered off, washed with ethanol (3 ml; denaturated) and dried (vacuum; 50 °C), yielding 0.26 g (23.4%) (B)-5-[(3-chlorophenyl)-lH-imidazol-l-yl- methyl]-lH-benzimidazole (E)-2-butenedioate (2:3).ethanolate (2:1); mp. 111.2°C (comp. 3).
PAPER

Improved synthesis of liarozole

J Ren, Y Sha, D Zhao, M CHENG - Chinese Journal of Medicinal …, 2006 - en.cnki.com.cn
... 1-yl)-methyl]-1H-benzimidazole(liarozole).Methods Starting from anisole,liarozole was synthesized
by Friedel-Crafts(acylation,)nitration,nucleophilic substitution,reduction and cyclization.Results
and conclusion The structure of liarozole was confirmed by()~1H-NMR and MS ...
see at..http://lib.syphu.edu.cn/71%E6%A0%A1%E5%86%85%E7%BD%91%E4%B8%93%E7%94%A8/zwlw%E5%85%A8%E6%96%87/60230.pdf
str1

str1

Paper

Conversion of the Laboratory Synthetic Route of the N-Aryl-2-benzothiazolamine R116010 to a Manufacturing Method

Chemical Process Research Department, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
Org. Proc. Res. Dev., 2001, 5 (5), pp 467–471
DOI: 10.1021/op0100201
 
PAPER
Synthesis and In Vitro Evaluation of3-(1-Azolylmethy1)-1H-indolesand
341-Azolyl-l-phenylmethyl)-1H-indolesasInhibitorsofP450arom
 
1 Vahlquist, A; Blockhuys, S; Steijlen, P; Van Rossem, K; Didona, B; Blanco, D; Traupe, H (2013). "Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: Results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial". The British journal of dermatology 170 (1): n/a. doi:10.1111/bjd.12626. PMID 24102348.
https://www.researchgate.net/profile/Marc_Le_Borgne/publication/8068537_2-_and_3-%28aryl%29%28azolyl%29methylindoles_as_potential_non-steroidal_aromatase_inhibitors/links/02e7e52fe95f662b24000000.pdf
Literature References: Inhibits cytochrome P450-dependent enzymes involved in steroid biosynthesis and retinoic acid catabolism. Prepn: A. H. M. Raeymaekers et al., EP 260744; eidem, US 4859684 (1988, 1989 both to Janssen). In vivo antitumor activity: R. Van Ginckel et al., Prostate 16, 313 (1990). Pharmacology and effect on steroid synthesis: J. Bruynseels et al., ibid., 345; and effect on retinoic acid: R. De Coster et al., J. Steroid Biochem. Mol. Biol. 43, 197 (1992). Clinical evaluation in prostate cancer: C. Mahler et al., Cancer 71, 1068 (1993); in psoriasis: P. Dockx et al., Br. J. Dermatol. 133, 426 (1995); in combination therapy for malignant brain tumors: M. E. Westarp et al., Onkologie 16, 22 (1993).
Liarozole
Liarozole.svg
Names
IUPAC name
6-[(3-Chlorophenyl)-imidazol-1-ylmethyl]-1H-benzimidazole
Identifiers
115575-11-6
ChemSpider54664
5210
Jmol interactive 3DImage
PubChem60652
Properties
C17H13ClN4
Molar mass308.77 g·mol−1
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C1=CC(=CC(=C1)Cl)C(C2=CC3=C(C=C2)N=CN3)N4C=CN=C4
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